Advancing physiology education by understanding the multiple dimensions of homeostasis.

Homeostasis of the internal environment has been considered the central organizing concept of physiology. However, current definitions of it in textbooks and online teaching sources do not sufficiently reflect how homeostasis serves its central unifying role. Meanwhile, scientific understanding of the functions of the body's structures at multiple levels (molecular, cell, tissue, organ, organ system, and organism) has advanced significantly, but the understanding of homeostasis is still in the same place. In this article, the author describes some issues and insufficiencies in teaching about homeostasis in physiology education and proposes that homeostasis needs to be understood in terms of four dimensions rather than a simple definition: internal, functional organization; functional manifestation; mechanism; and effect or consequence. Each dimension has two subdimensions or sides. Throughout the elucidation of these dimensions and subdimensions, the original meaning of homeostasis is reinforced, what is lost in current understanding of homeostasis becomes clear, some insufficiencies mentioned above are supplemented, new insights into homeostasis develop, and how the four dimensions of homeostasis can be applied to physiology education is exampled. This new, comprehensive conceptualization advances the understanding of homeostasis and can facilitate teaching and learning about homeostasis and physiology.

A better explanation of countercurrent multiplication in the formation of the corticopapillary osmotic gradient in the outer medulla.

Countercurrent multiplication (CCM) is widely accepted as the mechanism for the generation of the corticopapillary osmotic gradient in the outer medulla of mammalian kidneys. However, several issues in the literature cause the current explanations of CCM to be inefficient and incomplete. As a result, it is challenging to clearly explain CCM in physiology education. The goal of this article is to share a modified version of CCM with more understandable explanation in the hopes of motivating peer discussion, further improvement, and future research. To reach this goal, the logical processes leading to CCM are first analyzed, which results in a set of formulas that serve as the principles governing CCM. Next, the cessation of CCM is addressed to provide a complete picture of the modified version of CCM. Throughout these two steps, the issues mentioned above are identified and addressed so that how the modified version of CCM eliminates these issues becomes clear. The formulas mentioned above are provided in the Tables S1, S2, and S3 (all Supplemental material is available in the Supplemental Excel File at https://doi.org/10.6084/m9.figshare.23515614) to explain how the interstitial and intrathick ascending limb osmotic concentration (OC) values used in the figures in this article are simulated and how alternative OC values can be generated from Tables S1 and S2 to illustrate CCM.NEW & NOTEWORTHY Countercurrent multiplication is widely accepted as the mechanism for the generation of the corticopapillary osmotic gradient in the outer medulla of mammalian kidneys, but the current explanations of it in textbooks and the literature are inefficient and incomplete, leading to confusion for students. This article shares a modified version of countercurrent multiplication with more understandable explanation as a way of motivating peer discussion, further improvement, and future research.

Vascular function curve: confusion, clarification and new insights.

The vascular function curve (VFC) in cardiovascular physiology describes the relationship between the steady state venous return (VR in L/min, in the Y-axis) and the steady state right atrial pressure (RAP in mmHg, in the X-axis). However, in some literature, the RAP is considered the independent variable (IV) and the VR the dependent variable (DV), whereas in other literature, the VR is the IV and the RAP the DV. Because of this confusion, when the VFC is combined with the cardiac function curve (CFC), which describes the relationship between the steady state cardiac output and the RAP, it is not strange that the interpretations of the combination are problematic. Hence, in this article, we will trace the origin of the inconsistency, differentiate the VFC into two types based on who created them, and differentiate the RAP into RAP as the IV and DV respectively. Through these in-depth analyses, the confusion will be clarified and new insights into the combination of a VFC with the CFC will develop.

Six logical steps that connect the introduction of the Nernst equation to its clinical application.

The Nernst equation is key to understanding the electrophysiology of the cell membrane and the pathophysiology of K+ imbalances (i.e., hyperkalemia and hypokalemia). However, in our experience teaching medical students over the years, many students struggle to make connections between a brief introduction of the Nernst equation and its clinical application to K+ imbalances. This article aims to connect the introduction of the equation to its clinical application to understand K+ imbalances using six logical steps with detailed visual illustrations that make the connection explicit and cohesive. In addition, we highlight a few common areas related to the six steps that are often overlooked by both teachers and students. Students who are able to thoroughly demonstrate an understanding of all the six steps highlighted in this article will achieve mastery of this topic.NEW & NOTEWORTHY This article fills the gaps in teaching about the Nernst equation, which is important in medical physiology. Six logical steps are presented that connect the introduction of the equation to its clinical applications to hyperkalemia and hypokalemia, two conditions that can be life-threatening if left untreated. Only when students know how to apply the equation will their learning transition from surface to mastery.

A broader outlook to reduce pre-exam stress.

Stress, depression, and job burnout are plaguing the medical field. These issues have many causes, one of which is a stigma or the fear of being stigmatized that leads the sufferer to deny the problem or delay seeking help. In this article, I will share a recent story of how a mind adjustment from a negative view of the past failure to a broader outlook quickly and effectively reduced the pre-exam stress of a student in a class I am teaching.

How to Receive Criticism: Theory and Practice from Cognitive and Cultural Approaches.

Mistakes in clinical practice may have life-or-death consequences for patients. Training in how to give and receive feedback has been emphasized in medical education for decades, yet medical practitioners continue to struggle with these practices. Giving feedback is difficult because it is not easy for a receiver to receive feedback. Current training programs lack an in-depth understanding of the causes of why receiving feedback is not easy. The purposes of this article are to (1) fill this gap by identifying the shared weaknesses in human nature as the causes underlying the difficulty in receiving feedback, especially criticism, using a cognitive approach; (2) develop logical principles to treat the identified causes; (3) show the shared common wisdom of how to receive criticism through a multicultural approach; and finally, (4) address how these cognitive and multicultural approaches may facilitate receiving criticism in the field of medical education.

How Microelectrode Array-Based Chick Forebrain Neuron Biosensors Respond to Glutamate NMDA Receptor Antagonist AP5 and GABAA Receptor Antagonist Musimol.

We have established a long-term, stable primary chick forebrain neuron (FBN) culture on a microelectrode array platform as a biosensor system for neurotoxicant screening and for neuroelectrophysiological studies for multiple purposes. This paper reports some of our results, which characterize the biosensor pharmacologically. Dose-response experiments were conducted using NMDA receptor antagonist AP5 and GABAA receptor agonist musimol (MUS). The chick FBN biosensor (C-FBN-biosensor) responds to the two agents in a pattern similar to that of rodent counterparts; the estimated EC50s (the effective concentration that causes 50% inhibition of the maximal effect) are 2.3 µM and 0.25 µM, respectively. Intercultural and intracultural reproducibility and long-term reusability of the C-FBN-biosensor are addressed and discussed. A phenomenon of sensitization of the biosensor that accompanies intracultural reproducibility in paired dose-response experiments for the same agent (AP5 or MUS) is reported. The potential application of the C-FBN-biosensor as an alternative to rodent biosensors in shared sensing domains (NMDA receptor and GABAA receptor) is suggested.

Establishment of a Long-Term Chick Forebrain Neuronal Culture on a Microelectrode Array Platform.

The biosensor system formed by culturing primary animal neurons on a microelectrode array (MEA) platform is drawing an increasing research interest for its power as a rapid, sensitive, functional neurotoxicity assessment, as well as for many other electrophysiological related research purposes. In this paper, we established a long-term chick forebrain neuron culture (C-FBN-C) on MEAs with a more than 5 month long lifespan and up to 5 month long stability in morphology and physiological function; characterized the C-FBN-C morphologically, functionally, and developmentally; partially compared its functional features with rodent counterpart; and discussed its pros and cons as a novel biosensor system in comparison to rodent counterpart and human induced pluripotent stem cells (hiPSCs). Our results show that C-FBN-C on MEA platform 1) can be used as a biosensor of its own type in a wide spectrum of basic biomedical research; 2) is of value in comparative physiology in cross-species studies; and 3) may have potential to be used as an alternative, cost-effective approach to rodent counterpart within shared common functional domains (such as specific types of ligand-gated ion channel receptors and subtypes expressed in the cortical tissues of both species) in large-scale environmental neurotoxicant screening that would otherwise require millions of animals.

Prolonging life in chick forebrain-neuron culture and acquiring spontaneous spiking activity on a microelectrode array.

Various types of animal neurons were cultured on a microelectrode array (MEA) platform to form biosensors to detect potential environmental neurotoxins. For a large-scale screening tool, rodent MEA-based cortical-neuron biosensors would be very costly but chick forebrain neurons (FBNs) are abundant, cost-effective, and easy to dissect. However, chick FBNs have a lifespan of ~14 days in vitro and their spontaneous spike activity (SSA) has been difficult to develop and detect. We used a high-density neuron-glia co-culture on an MEA to prolong chick FBN lifetime to 3 months with lifetime-long SSA. A remarkable embryonic age-dependency in the culture's morphology, lifespan, and most features of SSA signal was discovered. Our results show the feasibility of developing a chick FBN-MEA biosensor and also establish a new electrophysiological platform for functional study of an in vitro neuronal network.

Decreased level of Nurr1 in heterozygous young adult mice leads to exacerbated acute and long-term toxicity after repeated methamphetamine exposure.

The abuse of psychostimulants, such as methamphetamine (METH), is prevalent in young adults and could lead to long-term adaptations in the midbrain dopamine system in abstinent human METH abusers. Nurr1 is a gene that is critical for the survival and maintenance of dopaminergic neurons and has been implicated in dopaminergic neuron related disorders. In this study, we examined the synergistic effects of repeated early exposure to methamphetamine in adolescence and reduction in Nurr1 gene levels. METH binge exposure in adolescence led to greater damage in the nigrostrial dopaminergic system when mice were exposed to METH binge later in life, suggesting a long-term adverse effect on the dopaminergic system. Compared to naïve mice that received METH binge treatment for the first time, mice pretreated with METH in adolescence showed a greater loss of tyrosine hydroxylase (TH) immunoreactivity in striatum, loss of THir fibers in the substantia nigra reticulata (SNr) as well as decreased dopamine transporter (DAT) level and compromised DA clearance in striatum. These effects were further exacerbated in Nurr1 heterozygous mice. Our data suggest that a prolonged adverse effect exists following adolescent METH binge exposure which may lead to greater damage to the dopaminergic system when exposed to repeated METH later in life. Furthermore, our data support that Nurr1 mutations or deficiency could be a potential genetic predisposition which may lead to higher vulnerability in some individuals.

NMDA receptors on non-dopaminergic neurons in the VTA support cocaine sensitization.

BACKGROUND: The initiation of behavioral sensitization to cocaine and other psychomotor stimulants is thought to reflect N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic plasticity in the mesolimbic dopamine (DA) circuitry. The importance of drug induced NMDAR mediated adaptations in ventral tegmental area (VTA) DA neurons, and its association with drug seeking behaviors, has recently been evaluated in Cre-loxp mice lacking functional NMDARs in DA neurons expressing Cre recombinase under the control of the endogenous dopamine transporter gene (NR1(DATCre) mice). METHODOLOGY AND PRINCIPAL FINDINGS: Using an additional NR1(DATCre) mouse transgenic model, we demonstrate that while the selective inactivation of NMDARs in DA neurons eliminates the induction of molecular changes leading to synaptic strengthening, behavioral measures such as cocaine induced locomotor sensitization and conditioned place preference remain intact in NR1(DATCre) mice. Since VTA DA neurons projecting to the prefrontal cortex and amygdala express little or no detectable levels of the dopamine transporter, it has been speculated that NMDA receptors in DA neurons projecting to these brain areas may have been spared in NR1(DATCre) mice. Here we demonstrate that the NMDA receptor gene is ablated in the majority of VTA DA neurons, including those exhibiting undetectable DAT expression levels in our NR1(DATCre) transgenic model, and that application of an NMDAR antagonist within the VTA of NR1(DATCre) animals still blocks sensitization to cocaine. CONCLUSIONS/SIGNIFICANCE: These results eliminate the possibility of NMDAR mediated neuroplasticity in the different DA neuronal subpopulations in our NR1(DATCre) mouse model and therefore suggest that NMDARs on non-DA neurons within the VTA must play a major role in cocaine-related addictive behavior.

How useful are stem cells in PD therapy?

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The onset of PD is usually after the age of 50. Clinical symptoms of PD are not manifested until 60-80% of dopaminergic neurons in the midbrain have been affected. Cell replacement has been a promising approach for the treatment of PD. Fetal mesencephalic dopaminergic neurons seemed to improve the motor disability in patients in some early studies. However, the clinical application of this approach may be limited by ethical and logistic concerns, as well as by side effects. On the other hand, embryonic stem (ES) cells are promising candidates because of their ability to provide an unlimited supply of specific cell types, their accessibility to genetic modifications, and their broad developmental potentials. Transplants of undifferentiated ES cells were able to proliferate and fully differentiate into dopaminergic neurons in a rodent PD model. One of the concerns though is the risk of tumor formation. The tumorigenic potential of ES cells seems to be greatly reduced when cells are predifferentiated into dopaminergic neurons in vitro before implantation. Recent developments in the induction of pluripotent stem cells from somatic adult cells provide a tremendous opportunity for this field. Initial success has been reported in a rodent PD model using iPS cells (induced pluripotent stem cells). However, whether this initial result can be successfully translated into human clinical studies still needs to be determined.